The invention relates to modification of behavior, particularly habitual or addictive behavior, using a combination of chemotherapeutic assistance and psychological counseling. More specifically, it relates to a three-stage protocol for replacing an undesired habit with a desired one.
Attempts to alter human behavioral patterns associated with addictions or compulsions are littered with failure. Programs designed to modify such habits as overeating, addiction to narcotics, alcoholism, and smoking are the basis for an industry with a turnover of billions of dollars a year. Some of these programs involve entirely psychological counseling and support. Others employ known chemical agents.
A large number of pharmacological agents that affect behavior is known. Perhaps one of the best known is the combination Fen-Phen used for many years to exert an anorectic effect to treat obesity. This combination of phentermine and fenfluramine was available until recently when the cardiopulmonary side effects of this medicament were considered unacceptable. Both of these components are related to amphetamines and are epinephrine analogs which can be used to combat fatigue and drowsiness. The use of, for example, donepezil to treat the symptoms of Alzheimer""s disease is also known. In short, a variety of agents known to affect the central nervous system have been used in various contexts to treat a number of indications related directly or indirectly to behaviors.
At present, however, there appears to be no established treatment that is adaptable generally to replacing undesired behaviors permanently with desired ones. The present invention provides such a protocol.
The protocol of the present invention, in addition to correcting undesirable habitual behavior, also restores the normal balance of the various neurotransmitters mediated by norepinephrine, dopamine, serotonin and acetyl choline. By virtue of the imbalance in the behavior of these neurotransmitters, chronic conditions such as cancer and Alzheimer""s disease may occur. Therefore, by restoring the balance, the protocols of the invention operate as preventatives for these conditions.
The invention provides a protocol that can be adapted to replace a behavioral pattern that is ingrained and undesired with a desired one the desired behavior may include simply avoidance of the undesirable activity. The protocol can be applied to humans and to other mammals. The protocol of the invention can be modified as described herein to treat individuals who are habitual gamblers, smokers, alcoholics, sufferers of incapacitating fatigue, narcotics addicts, and the like. It can also be used to train animals, such as domestic pets. The invention protocol also relates to a method to prevent the onset of chronic conditions such as Alzheimer""s disease and cancer by restoring appropriate neurotransmitter balance. The capacity of the protocol to prevent cancer may be mediated by a positive effect on the immune system.
The invention relates to a three-stage protocol the length of which will vary with the nature of the subject treated.
The first stage comprises acute treatment with effective amounts of compounds that augment the activity of and generally affect the amine neurotransmitters that are associated with the sympathetic nervous system and which influence implicit memory. This treatment may be supplemented with specific aids as dictated by the condition of the subject; for example, a nicotine patch may be useful where the undesired behavior is smoking.
The second stage involves maintaining chemotherapy with these amine neurotransmitter augmenting compounds but adds a component of psychology/supportive therapy in the case of humans, and training or otherwise effecting or conditioning a behavioral adjustment in the case of nonhuman animals. For nonhuman animals this may involve an indirect intervention, e.g., modifying the behavior of the owner.
The third stage comprises administering an acetylcholinesterase (AChase) inhibitor along with the compounds described above with respect to stages I and II. The third stage mimics the psychological condition of rapid eye movement (REM) sleep.
The protocol may be supplemented by a superimposed treatment whereby diurnal variation is mimicked by administration of a corticosteroid, such as prednisone.
The subjects for which the invention protocol is intended are human or animal subjects who would be benefited by modification of behavior to overcome what might simply be called a xe2x80x9cbad habit.xe2x80x9d The habits can be internal or external. An internal habit arises by virtue of repetitive behavior unrelated to a direct metabolic effect of an external agent. An external habit further involves an interaction with an external metabolic agent. External habits include narcotics addiction and smoking; internal habits would be exemplified by gambling and overeating. Of course, external habits may be reinforced by an internal habit mechanism as well. As will be seen, where a habit is internal, stage I treatment consists only of stimulators of the sympathetic nervous system in the form of compounds that stimulate amine neurotransmitters, optionally along with agents to control possible side effects of these drugs in cases where they are needed. For treatment of habits which have an external component, however, the subject is supplied with sufficient amounts of the external substance, or with a specific substitute therefor, to ameliorate withdrawal symptoms.
In general, the habitual behavior is controlled by xe2x80x9cimplicit memory.xe2x80x9d As defined herein, xe2x80x9cimplicit memoryxe2x80x9d is the unintentional recall of events or activities that influence behavior. Implicit memory is controlled by amine neurotransmitters, most prominently serotonin, norepinephrine, and dopamine. Implicit memory is brought to bear in behaviors that are permanently available and relatively unconsciously controlled. Exemplary behaviors of this type often include a physical component. Motor skills such as riding a bicycle, skiing, swimming, ice skating and the like, once learned, are essentially permanent. Conscious mechanisms are not required to bring them to recall.
On the other hand, xe2x80x9cexplicit memoryxe2x80x9d as defined herein relates to a conscious and deliberate recall of recent events and volitional behavior. In general, this type of memory is controlled by a single neurotransmitter, acetylcholine. In stage III of the protocol described herein, the explicit memory is stimulated along with the implicit memory, thus mimicking the transfer of elements from explicit to implicit memory similar to that which occurs in REM sleep. This transfer, in general, permits replacement of a xe2x80x9cgoodxe2x80x9d habit which has been implanted in the explicit memory into the habitual realm of the implicit memory. Thus, the behavior patterns explicitly learned in stage II of the invention protocol are transferred into the implicit memory in stage III.
In addition to subjects who are affected by undesirable habitual behavior, the protocols of the invention can be used to restore appropriate neurotransmitter balance in anyone where imbalance occurs. It is believed that imbalance in neurotransmitters negatively affects the immune system, which in turn lowers the resistance of the individual to the onset of malignancy and that this imbalance also contributes to the onset of Alzheimer""s disease.
As set forth above, the method of the invention is a protocol that involves three stages of treatment. The first stage, initial therapy, is designed to activate the implicit memory to make the habitual behavior available for modification. The pharmacological agents useful in this stage are compounds that stimulate amine neurotransmitters of the sympathetic nervous system. In general, these compounds are amines which are related to the three major neurotransmitters, serotonin, norepinephrine, and dopamine. Included among these are compounds related to norepinephrine such as ethylnorepinephrine, metaraninol, tyramine, hydroxyamphetamine, methoxamine, albuterol, metamphetamine, benzphetamine, phenylpropanolamine, phentermine, fenfluramine (Pondamin) and dexfenfluramine (Redux), diethylpropion, phentriazine and phendimetriazine. Preferred among these is a combination of phentermine (Ionamin, Adipex) and fenfluramine (Pondamin).
Also useful in stage I is administration of a selective serotonin reuptake inhibitor (SSRI) such as citalopram (Celexa), fluoxetine HCl (Prozac), fluoxamine maleate (Luvox), paroxetine HCl (Paxil) and sertraline HCl (Zoloft). Also useful are drugs which affect dopamine receptors, such as apomorphine and its derivatives.
The dosage of the compounds administered to stimulate the sympathetic nervous system and implicit memory will depend on the specific pharmacologic agent chosen, the condition of the subject, and the judgment of the physician or veterinarian. However, for the combination of phentermine and fenfluramine, preferred dosage ranges are approximately 10 mg fenfluramine and 15-30 mg of phentermine daily. Typical dosages of citalopram are of the order of 10 mg daily.
In addition to the general implicit memory stimulators of the types set forth above, supplemental medication may also be indicated. Where the subject shows severe dependency, or is desirous of modifying a multiplicity of habits, an adrenergic agonist selective for the xcex12 receptor is also desirable. These compounds are typically imidazolines and are typified by clonidine. The effects of clonidine appear to result from activation of the xcex12 receptors in the lower brain stem region, and clonidine has been used previously in treating subjects addicted to drugs, alcohol and tobacco. Clonidine is considered to help ameliorate adverse sympathetic nervous activity associated with withdrawal from these agents. If clonidine is used, typical dosage levels are on the order of 0.1-0.4 mg orally, daily. It can also be administered as a patch.
Other supplementary medications which are employed in stage I are specific for particular addictions. Thus, a nicotine patch may be useful where the habit to be shed is smoking; a low-dose nicotine patch which provides 7 mg is typical, alternate dosage levels can also be used. If the habit to be shed is alcoholism, a supplementary dose of benzodiazapine may also be helpful.
For treatment of obesity due to overeating, the subject is generally placed on a lowcalorie or very-low-calorie diet. One such diet is marketed as Nutrimed which is a high-protein, low-carbohydrate, semistarvation fast. The standard protocol for providing Nutrimed regimens utilizes five xe2x80x9cmilkshakexe2x80x9d like compositions per day to supply 420 kC. It is helpful to modify this regimen to include, as a substitute for one or two of the xe2x80x9cshakes,xe2x80x9d a small meal so that the subject can experience the social interaction associated with dining. The inclusion of this modification has been helpful in ensuring compliance. The use of this regimen, modified or unmodified, is also sometimes helpful in subjects who are not obese and inclusion of this regimen in the therapeutic protocol has been found successful in a number of instances.
In general, very low calorie diets generally successfully block hunger driven by habit rather than by appetite. Such habit-driven hunger is an example of behavior controlled by implicit memory but governed by an external metabolic agent. Used in conjunction with therapies for treating external habits, very low calorie diets can supplement the effectiveness of these therapies.
In addition, if the subject has other physiological conditions that aggravate possible side effects of the stimulators of the implicit memory, offsetting medications such as xcex2-blockers, which reduce heart rate, lower blood pressure, and ameliorate hypertension may be added to the protocol. Typical xcex2-blockers which may be provided to ameliorate hypertension include atenolol (Tenormin), usually in dosages of 12.5-50 mg.
With regard to hypertension, however, a preferable treatment may include vasodilators such as amlodipine besylate, marketed as Norvasc(copyright) and nifedipine marketed as Procardia(copyright) or Adalat(copyright).
Thus, stage I involves, in general, stimulation of the implicit memory using appropriate compounds that stimulate amine neurotransmitters associated with the sympathetic nervous system supplemented with additional medications if desirable. The duration of stage I will vary from subject to subject. It may be as short as 1-3 weeks but may extend longer.
Stage II, which provides the basis for long-term control, continues the administration of stimulators of the implicit memory as done in stage I. The dosages and protocols for administration of these stimulators may be identical to that of stage I or may be modified according to the response perceived in the subject. In addition, medications which are used to control adverse effects of the primary effectors of implicit memory activity may also be used. Thus, for example, for hypertension, the administration of xcex2-blockers may be continued.
Stage II differs from stage I in that a component of psychological and supportive therapy is added. Such therapies can be adapted to apply to non human animals as well. Most auxiliary medicaments are typically dropped. Conventional psychological and supportive treatment modalities are employed. These modalities are designed to affect the explicit memory and provide the basis for the deliberate recall of recent events that will be employed in stage III to result in permanent behavior modification. The psychological and supportive therapy may be as simple as consultations with the attending physician or may be more formal in nature, such as psychiatric treatment. For humans, generally a professional will provide this psychological and supportive therapy, although this could also be achieved through group counseling or intervention with respect to a care provider or other individual or individuals who routinely or often or sporadically interact with the subject of treatment. This is often the case where the subject is a nonhuman animal. In addition to professional interaction with the nonhuman animal, the professional or other intervention may be with respect, for example, to the owner of the animal who, in turn, by alteration of his/her behavior toward the subject, effects this psychological support.
The duration of stage II is also variable, but is typically several months to more than two years, most typically approximately 4-8 months. This stage is most susceptible to external influences, and the duration and intensity of the psychological and supportive component will vary depending in the case of human subjects, on the other circumstances in which the subject finds himself or herself. There is no theoretical upper limit to the duration of this stage, and Stage III can begin at any time, provided the effect of Stage II has been accomplished.
In stage III, the transfer of the behavior placed into explicit memory in stage II into the implicit memory occurs. In stage III, stimulation of the implicit memory is continued as in stage II, with suitable variation in dosage and regimen if indicated. Stage III involves the addition of administration of an acetylcholine esterase (AChase) inhibitor such as donepezil. Other currently available AChase inhibitors include tacrine and pyridostigmine bromide. Also available are rivastigmine tartrate, marketed as Exelon(copyright) and galantamine hydrobromide, marketed as Reminyl(copyright). Any AChase inhibitor or combination is within the scope of the invention. In stage III, both the implicit and explicit memory are stimulated, thus mimicking REM sleep. During this stage, the replacement of the learned behavior from stage II into the implicit memory is accomplished. The duration of stage III also varies from subject to subject, but is typically on the order of 6-12 months; stage III is continued until successful results are achieved.
Once the three stages are completed, the protocol is successful in a permanent alteration of behavior. The protocol is apparently successful in treating over 1400 subjects with behavior characteristics that include overeating, smoking tobacco, chewing tobacco, alcoholism, drug use, gambling, repetitive motion disorder and fatigue, who have either completed all stages of the treatment or are currently in stage II.
As will be apparent from the foregoing, the timing of stage I, stage II and stage III is quite variable depending on factors not necessarily under the control of the practitioner. The duration of any particular stage is dependent on, for example, the level of social support available to the subject, whether or not there are multiple addictions, the presence or absence of physical or psychological problems, and the like. Thus, although suggested durations are provided above, it is anticipated that such times will vary widely. Determination of the appropriate timing for each stage is well within ordinary skill of the practitioner.
Optionally, superimposed on the above protocol at any stage or at more than one stage is treatment to mimic diurnal fluctuations in metabolism by administering a corticosteroid. Typical protocols include administering 5 mg of prednisone at 7 a.m. and 3 p.m. for the first month in which this aspect of the treatment is employed, and later reducing the dosage regimen to 5 mg at 7 a.m. and 2.5 mg at 3 p.m.
The examples below illustrate typical protocols useful in the invention. In addition, the following dosages are typical as a preferred embodiment:
for phentermine (Adipex-P 37.5) one-half pill or one pill daily; this product contains 30 mg phentermine per pill;
for fenfluramine, one-quarter, one-half, or (rarely) one pill daily of a 20-mg tablet;
for citalopram (Celexa), one-fourth or one-half pill daily of a 20-mg tablet (if the subject indicates use of a serotonin uptake inhibitor, one pill daily may be prescribed);
for donepezil (Aricept), one-fourth to one-half pill daily as a 5-mg tablet.
The following examples are intended to illustrate but not to limit the invention.